This project focuses on the role of signal transduction mechanisms in Long-term Potentiation (LTP) and memory formation. Lately we have been exploring the role of the Mitogen-Activated Protein Kinase (MAPK) family of signal transduction cascades in hippocampal synaptic plasticity and learning. We initiated our studies in this area about 10 years ago by determining that the Extracellular-Signal Regulated Kinase (ERK) isoforms of MAPK are activated with LTP-inducing stimulation in hippocampal slices, and that ERK activation is necessary for NMDA receptor-dependent LTP in area CA1. We then transitioned to studies in the behaving animal and discovered that ERK is activated in the hippocampus with contextual associative conditioning, and that ERK activation is necessary for fear conditioning and for spatial learning in the Morris water maze. Studies from a wide variety of laboratories have now shown that MAPK signaling is involved in many forms of synaptic plasticity and learning, in essentially every species that has so far been examined. Given the clear importance of understanding the roles and regulation of ERK in synaptic plasticity and learning, for the next project period we propose to continue our investigations into the upstream regulators and downstream targets of ERK in the hippocampus. We will pursue the following three Specific Aims: 1: To test the hypothesis of a role for the scaffolding protein Kinase Suppressor of Ras (KSR) in hippocampal ERK activation, LTP, and hippocampus-dependent memory. 2: To test the hypothesis that Histone Acetyl Transferases (HATs) are a target of ERK regulation in the hippocampus. 3: To test the hypothesis that the dual-specificity MAPK phosphatase MKP-3 is a negative feedback regulator of ERK. These studies will give us insights into key functional loci in the hippocampal ERK MAP Kinase cascade, a new signal transduction pathway involved in transcriptional regulation, synaptic plasticity, and memory formation.